MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that play critical roles in development and disease. Target-directed miRNA degradation (TDMD), a pathway in which miRNAs that bind to specialized targets with extensive complementarity are rapidly decayed, has emerged as a potent mechanism of controlling miRNA levels. Nevertheless, the biological role and scope of miRNA regulation by TDMD in mammals remains poorly understood. To address these questions, we generated mice with constitutive or conditional deletion of Zswim8, which encodes an essential TDMD factor. Loss of Zswim8 resulted in developmental defects in the heart and lungs, growth restriction, and perinatal lethality. Small RNA sequencing of embryonic tissues revealed widespread miRNA regulation by TDMD and greatly expanded the known catalog of miRNAs regulated by this pathway. These experiments also uncovered novel features of TDMD-regulated miRNAs, including their enrichment in cotranscribed clusters and examples in which TDMD underlies “arm switching,” a phenomenon wherein the dominant strand of a miRNA precursor changes in different tissues or conditions. Importantly, deletion of two miRNAs, miR-322 and miR-503, rescued growth of Zswim8-null embryos, directly implicating the TDMD pathway as a regulator of mammalian body size. These data illuminate the broad landscape and developmental role of TDMD in mammals.

中文翻译：

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靶向 microRNA 降解调节哺乳动物发育 microRNA 表达和胚胎生长

MicroRNA (miRNA) 是基因表达的转录后调节因子，在发育和疾病中发挥着关键作用。靶向 miRNA 降解 (TDMD) 是一种与具有广泛互补性的特定靶点结合的 miRNA 快速降解的途径，已成为控制 miRNA 水平的有效机制。然而，TDMD 在哺乳动物中调节 miRNA 的生物学作用和范围仍然知之甚少。为了解决这些问题，我们培育了Zswim8组成型或条件性缺失的小鼠，Zswim8 编码重要的 TDMD 因子。Zswim8的缺失会导致心脏和肺部的发育缺陷、生长受限和围产期死亡。胚胎组织的小 RNA 测序揭示了 TDMD 广泛的 miRNA 调控，并极大地扩展了受该途径调控的已知 miRNA 目录。这些实验还揭示了 TDMD 调节的 miRNA 的新特征，包括它们在共转录簇中的富集以及 TDMD 是“臂转换”基础的例子，“臂转换”是一种 miRNA 前体的主导链在不同组织或条件下发生变化的现象。重要的是，删除两个 miRNA（miR-322 和 miR-503）可以挽救Zswim8缺失胚胎的生长，这直接表明 TDMD 通路是哺乳动物体型的调节因子。这些数据阐明了 TDMD 在哺乳动物中的广阔前景和发育作用。